Skip to main content
SpringerLink
Log in

Novel Targeted Treatment Approaches in Pancreatic Cancer

  • Chapter
  • First Online:
Textbook of Gastrointestinal Oncology

  • 854 Accesses

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related death in the United States. Since the hallmark clinical trial in 1997 that showed superiority of gemcitabine over 5-fluorouracil, gemcitabine has been the mainstay of treatment of PDAC, either as single agent or in combination with other treatments. FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) was also recently introduced for the treatment of patients with a good performance status. However, despite large cancer sequencing initiatives in the past decade that have allowed for a better understanding of the molecular biology of PDAC, highly efficacious therapies, especially in the setting of locally advanced and metastatic disease, are still lacking. Although several target agents have been investigated in PDAC, almost all have failed to demonstrate a survival benefit in late-phase clinical trials. In this chapter, we will review novel target agents that were evaluated in clinical trials for the treatment of PDAC, focusing on small-molecule therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997;349(9050):485–9.

    Article  CAS  PubMed  Google Scholar 

  2. O'Reilly EM. Refinement of adjuvant therapy for pancreatic cancer. JAMA. 2010;304(10):1124–5.

    Article  CAS  PubMed  Google Scholar 

  3. Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473–81.

    Article  CAS  PubMed  Google Scholar 

  4. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    Article  CAS  PubMed  Google Scholar 

  5. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.

    Article  CAS  Google Scholar 

  6. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2012;2(3):260–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ueno H, Ioka T, Ikeda M, Ohkawa S, Yanagimoto H, Boku N, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31(13):1640–8.

    Article  CAS  PubMed  Google Scholar 

  8. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53(4):549–54.

    Article  CAS  PubMed  Google Scholar 

  9. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  10. Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L. Yeo CJ, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025–33.

    CAS  PubMed  Google Scholar 

  11. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271(5247):350–3.

    Article  CAS  PubMed  Google Scholar 

  12. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491(7424):399–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xiong HQ, Abbruzzese JL. Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Semin Oncol. 2002;29(5 Suppl 14):31–7.

    Article  CAS  PubMed  Google Scholar 

  17. Senderowicz AM, Johnson JR, Sridhara R, Zimmerman P, Justice R, Pazdur R. Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. Oncology (Williston Park). 2007;21(14):1696–706; discussion 706-9, 712, 715.

    Google Scholar 

  18. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6.

    Article  CAS  PubMed  Google Scholar 

  19. da Cunha Santos G, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010;116(24):5599–607.

    Article  CAS  PubMed  Google Scholar 

  20. Carneiro BA, Brand RE, Fine E, Knop RH, Khandekar JD, Uhlig W, et al. Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma. Cancer Investig. 2007;25(5):366–71.

    Article  CAS  Google Scholar 

  21. Fountzilas G, Bobos M, Kalogera-Fountzila A, Xiros N, Murray S, Linardou H, et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Investig. 2008;26(8):784–93.

    Article  CAS  Google Scholar 

  22. Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008;9(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  23. Kullmann F, Hollerbach S, Dollinger MM, Harder J, Fuchs M, Messmann H, et al. Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer. 2009;100(7):1032–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28(22):3605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fensterer H, Schade-Brittinger C, Muller HH, Tebbe S, Fass J, Lindig U, et al. Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP). Ann Oncol. 2013;24(10):2576–81.

    Article  CAS  PubMed  Google Scholar 

  26. Graeven U, Kremer B, Sudhoff T, Killing B, Rojo F, Weber D, et al. Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. Br J Cancer. 2006;94(9):1293–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Strumberg D, Schultheis B, Scheulen ME, Hilger RA, Krauss J, Marschner N, et al. Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer. Investig New Drugs. 2012;30(3):1138–43.

    Article  CAS  Google Scholar 

  28. Su D, Jiao SC, Wang LJ, Shi WW, Long YY, Li J, et al. Efficacy of nimotuzumab plus gemcitabine usage as first-line treatment in patients with advanced pancreatic cancer. Tumour Biol. 2014;35(3):2313–8.

    Article  CAS  PubMed  Google Scholar 

  29. Kimura K, Sawada T, Komatsu M, Inoue M, Muguruma K, Nishihara T, et al. Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res. 2006;12(16):4925–32.

    Article  CAS  PubMed  Google Scholar 

  30. Safran H, Iannitti D, Ramanathan R, Schwartz JD, Steinhoff M, Nauman C, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Investig. 2004;22(5):706–12.

    Article  CAS  Google Scholar 

  31. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Kunz J, Beger HG, et al. Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol. 1993;24(10):1127–34.

    Article  CAS  PubMed  Google Scholar 

  32. Harder J, Ihorst G, Heinemann V, Hofheinz R, Moehler M, Buechler P, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21(41):6255–63.

    Article  CAS  PubMed  Google Scholar 

  34. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–43.

    Article  CAS  PubMed  Google Scholar 

  35. Safran H, Miner T, Resnick M, Dipetrillo T, McNulty B, Evans D, et al. Lapatinib/gemcitabine and lapatinib/gemcitabine/oxaliplatin: a phase I study for advanced pancreaticobiliary cancer. Am J Clin Oncol. 2008;31(2):140–4.

    Article  CAS  PubMed  Google Scholar 

  36. Safran H, Miner T, Bahary N, Whiting S, Lopez CD, Sun W, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol. 2011;34(1):50–2.

    Article  CAS  PubMed  Google Scholar 

  37. Wu Z, Gabrielson A, Hwang JJ, Pishvaian MJ, Weiner LM, Zhuang T, et al. Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2015;76(6):1309–14.

    Article  CAS  PubMed  Google Scholar 

  38. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 2001;61(1):131–7.

    CAS  PubMed  Google Scholar 

  39. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22(8):1430–8.

    Article  CAS  PubMed  Google Scholar 

  40. Wang D, Boerner SA, Winkler JD, LoRusso PM. Clinical experience of MEK inhibitors in cancer therapy. Biochim Biophys Acta. 2007;1773(8):1248–55.

    Article  CAS  PubMed  Google Scholar 

  41. Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG. Novel targets in solid tumors: MEK inhibitors. Clin Adv Hematol Oncol. 2006;4(11):831–6.

    PubMed  Google Scholar 

  42. Baccarini M. Second nature: biological functions of the Raf-1 "kinase". FEBS Lett. 2005;579(15):3271–7.

    Article  CAS  PubMed  Google Scholar 

  43. Hirano T, Shino Y, Saito T, Komoda F, Okutomi Y, Takeda A, et al. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Oncogene. 2002;21(38):5923–8.

    Article  CAS  PubMed  Google Scholar 

  44. Gysin S, Lee SH, Dean NM, McMahon M. Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 2005;65(11):4870–80.

    Article  CAS  PubMed  Google Scholar 

  45. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Investig New Drugs. 2012;30(3):1216–23.

    Article  CAS  Google Scholar 

  46. Infante JR, Papadopoulos KP, Bendell JC, Patnaik A, Burris HA 3rd, Rasco D, et al. A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours. Eur J Cancer. 2013;49(9):2077–85.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996;93(8):3636–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ng SSW, Tsao MS, Chow S, Hedley DW. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res. 2000;60(19):5451–5.

    CAS  PubMed  Google Scholar 

  49. Perugini RA, McDade TP, Vittimberga FJ Jr, Callery MP. Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J Surg Res. 2000;90(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  50. O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2015;26(12):2505.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730–8.

    Article  CAS  PubMed  Google Scholar 

  52. Richards DA, Kuefler PR, Becerra C, Wilfong LS, Gersh RH, Boehm KA, et al. Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study. Investig New Drugs. 2011;29(1):144–53.

    Article  CAS  Google Scholar 

  53. Rexahn Pharmaceuticals Inc. A safety and efficacy study of RX-0201 Plus Gemcitabine in metastatic pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01028495.

  54. Array BioPharma. Safety, Pharmacokinetics and Pharmacodynamics of BEZ235 Plus MEK162 in Selected Advanced Solid Tumor Patients. In: Clinicaltrialsgov. Available at: https://clinicaltrials.gov/ct2/show/NCT01337765.

  55. UNC Lineberger Comprehensive Cancer Center. BKM120 + mFOLFOX6 in Advanced Solid Tumors With Expansion Cohort Pancreatic Cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01571024.

  56. Asano T, Yao Y, Zhu J, Li D, Abbruzzese JL, Reddy SA. The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. Biochem Biophys Res Commun. 2005;331(1):295–302.

    Article  CAS  PubMed  Google Scholar 

  57. Bruns CJ, Koehl GE, Guba M, Yezhelyev M, Steinbauer M, Seeliger H, et al. Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res. 2004;10(6):2109–19.

    Article  CAS  PubMed  Google Scholar 

  58. Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27(2):193–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kordes S, Klumpen HJ, Weterman MJ, Schellens JH, Richel DJ, Wilmink JW. Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2015;75(6):1135–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059–87.

    Article  CAS  PubMed  Google Scholar 

  62. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903–11.

    Article  PubMed  Google Scholar 

  63. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54.

    Article  CAS  PubMed  Google Scholar 

  64. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846–51.

    Article  CAS  PubMed  Google Scholar 

  66. Di Marco M, Macchini M, Vecchiarelli S, Sina S, Biasco G. Hedgehog signaling: from the cuirass to the heart of pancreatic cancer. Pancreatology. 2012;12(4):388–93.

    Article  CAS  PubMed  Google Scholar 

  67. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 2008;14(19):5995–6004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Singh BN, Fu J, Srivastava RK, Shankar S. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One. 2011;6(11):e27306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Van Laethem JL. Effect on tumor perfusion of a chemotherapy combining Gemcitabine and Vismodegib before surgery in pancreatic cancer (NEOPACHI-001). In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01713218.

  71. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(8):2502–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. National Cancer Institute (NCI). Vismodegib and Gemcitabine Hydrochloride in Treating Patients With Advanced Pancreatic Cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01195415.

  73. National Cancer Institute (NCI). Gemcitabine Hydrochloride With or Without Vismodegib in Treating Patients With Recurrent or Metastatic Pancreatic Cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01064622.

  74. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, et al. Randomized phase Ib/II study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015;33(36):4284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sidney Kimmel Comprehensive Cancer Center. Hedgehog inhibitors for metastatic adenocarcinoma of the pancreas. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01088815.

  76. National Cancer Institute (NCI). GDC-0449 and Erlotinib hydrochloride with or without Gemcitabine Hydrochloride in treating patients with metastatic pancreatic cancer or solid tumors that cannot be removed by surgery. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT00878163.

  77. Mayo Clinic. Sirolimus and Vismodegib in Treating Patients With Solid Tumors or Pancreatic Cancer That is Metastatic or Cannot Be Removed By Surgery. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01537107.

  78. Infinity Pharmaceuticals Inc. A Study Evaluating IPI-926 in Combination With Gemcitabine in Patients With Metastatic Pancreatic Cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01130142.

  79. Andrew Ko. FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01383538.

  80. Ko AH, LoConte N, Tempero MA, Walker EJ, Kate Kelley R, Lewis S, et al. A phase I study of FOLFIRINOX Plus IPI-926, a Hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas. 2016;45(3):370–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhou J, Quinlan M, Hurh E, Sellami D. Exposure-response analysis of Sonidegib (LDE225), an oral inhibitor of the Hedgehog signaling pathway, for effectiveness and safety in patients with advanced solid tumors. J Clin Pharmacol. 2016;20.

    Google Scholar 

  82. Irvine DA, Zhang B, Kinstrie R, Tarafdar A, Morrison H, Campbell VL, et al. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep. 2016;6:25476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sidney Kimmel Comprehensive Cancer Center. Gemcitabine + Nab-paclitaxel With LDE-225 (Hedgehog Inhibitor) as Neoadjuvant therapy for pancreatic adenocarcinoma. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01431794.

  84. Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003;3(10):756–67.

    Article  CAS  PubMed  Google Scholar 

  85. Sundaram MV. The love-hate relationship between Ras and Notch. Genes Dev. 2005;19(16):1825–39.

    Article  CAS  PubMed  Google Scholar 

  86. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003;3(6):565–76.

    Article  CAS  PubMed  Google Scholar 

  87. De Jesus-Acosta A, Laheru D, Maitra A, Arcaroli J, Rudek MA, Dasari A, et al. A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. Investig New Drugs. 2014;32(4):739–45.

    Article  CAS  Google Scholar 

  88. National Cancer Institute (NCI). Gamma-Secretase Inhibitor RO4929097 and Gemcitabine hydrochloride in treating patients with advanced solid tumors. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01145456.

  89. National Cancer Institute (NCI). RO4929097 Before surgery in treating patients with pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01192763.

  90. Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol. 2012;30(19):2307–13.

    Article  CAS  PubMed  Google Scholar 

  91. Cancer Research UK. MK0752 and Gemcitabine hydrochloride in treating patients with stage III and IV pancreatic cancer that cannot be removed by surgery. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01098344.

  92. Smith DC, Eisenberg PD, Manikhas G, Chugh R, Gubens MA, Stagg RJ, et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin Cancer Res. 2014;20(24):6295–303.

    Article  CAS  PubMed  Google Scholar 

  93. OncoMed Pharmaceuticals Inc. Study of Gemcitabine, Abraxane® Plus Placebo Versus Gemcitabine, Abraxane® Plus 1 or 2 truncated courses of Demcizumab in subjects with 1st-line metastatic pancreatic ductal Adenocarcinoma (YOSEMITE). In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT02289898.

  94. OncoMed Pharmaceuticals Inc. A Study of Gemcitabine and Demcizumab (OMP-21M18) with or without Abraxane® as 1st-line treatment in subjects with locally advanced or metastatic pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01189929.

  95. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56(23):5360–4.

    CAS  PubMed  Google Scholar 

  96. Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, et al. Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res. 2000;60(2):409–16.

    CAS  PubMed  Google Scholar 

  97. Tentori L, Graziani G. Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol Res. 2005;52(1):25–33.

    Article  CAS  PubMed  Google Scholar 

  98. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.

    Article  CAS  PubMed  Google Scholar 

  99. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.

    Article  CAS  PubMed  Google Scholar 

  100. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9.

    Article  CAS  PubMed  Google Scholar 

  101. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.

    Article  CAS  PubMed  Google Scholar 

  102. Gemcitabine Hydrochloride and Cisplatin with or without Veliparib or Veliparib alone in treating patients with locally advanced or metastatic pancreatic cancer [database on the Internet]. Available from https://clinicaltrials.gov/ct2/show/NCT01585805. Identifier NCT01585805.

  103. Study to assess the safety & tolerability of a PARP inhibitor in combination with Gemcitabine in pancreatic cancer [database on the Internet]. Available from https://clinicaltrials.gov/ct2/show/NCT00515866. Identifier: NCT01585805.

  104. Hakam A, Fang Q, Karl R, Coppola D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci. 2003;48(10):1972–8.

    Article  CAS  PubMed  Google Scholar 

  105. Bergmann U, Funatomi H, Yokoyama M, Beger HG, Korc M. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res. 1995;55(10):2007–11.

    CAS  PubMed  Google Scholar 

  106. Vaccaro V, Melisi D, Bria E, Cuppone F, Ciuffreda L, Pino MS, et al. Emerging pathways and future targets for the molecular therapy of pancreatic cancer. Expert Opin Ther Targets. 2011;15(10):1183–96.

    Article  CAS  PubMed  Google Scholar 

  107. Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ Jr, Rocha-Lima CM, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834–42.

    Article  CAS  PubMed  Google Scholar 

  108. Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26(5):921–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tabernero J, Chawla SP, Kindler H, Reckamp K, Chiorean EG, Azad NS, et al. Anticancer activity of the type I insulin-like growth factor receptor antagonist, ganitumab, in combination with the death receptor 5 agonist, conatumumab. Target Oncol. 2015;10(1):65–76.

    Article  PubMed  Google Scholar 

  110. Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol. 2004;4(4):333–9.

    Article  CAS  PubMed  Google Scholar 

  111. Philip PA, Goldman B, Ramanathan RK, Lenz HJ, Lowy AM, Whitehead RP, et al. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). Cancer. 2014;120(19):2980–5.

    Article  CAS  PubMed  Google Scholar 

  112. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10(10):683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. El-Khoueiry ABNY, Yang D, Cole S, Kahn M, Zoghbi M, Berg J, Fujimori M, Inada T, Kouji H, Lenz H. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. 2013 ASCO Annual Meeting. 2013;J Clin Oncol 31, 2013 (suppl; abstr 2501). Available through: http://meetinglibrary.asco.org/content/115980-132.

  114. Prism Pharma Co. Ltd. Safety and Efficacy Study of PRI-724 Plus Gemcitabine in Subjects With Advanced or Metastatic Pancreatic Adenocarcinoma. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01764477.

  115. Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, et al. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 2001;61(10):4143–54.

    CAS  PubMed  Google Scholar 

  116. Trachte AL, Suthers SE, Lerner MR, Hanas JS, Jupe ER, Sienko AE, et al. Increased expression of alpha-1-antitrypsin, glutathione S-transferase pi and vascular endothelial growth factor in human pancreatic adenocarcinoma. Am J Surg. 2002;184(6):642–7; discussion 7-8.

    Article  CAS  PubMed  Google Scholar 

  117. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  118. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005;23(31):8033–40.

    Article  CAS  PubMed  Google Scholar 

  119. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28(22):3617–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ko AH, Venook AP, Bergsland EK, Kelley RK, Korn WM, Dito E, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2010;66(6):1051–7.

    Article  CAS  PubMed  Google Scholar 

  121. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.

    Article  CAS  PubMed  Google Scholar 

  122. Ko AH, Youssoufian H, Gurtler J, Dicke K, Kayaleh O, Lenz HJ, et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Investig New Drugs. 2012;30(4):1597–606.

    Article  CAS  Google Scholar 

  123. Starling N, Watkins D, Cunningham D, Thomas J, Webb J, Brown G, et al. Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5499–505.

    Article  CAS  PubMed  Google Scholar 

  124. Watkins DJ, Starling N, Cunningham D, Thomas J, Webb J, Brown G, et al. The combination of a chemotherapy doublet (gemcitabine and capecitabine) with a biological doublet (bevacizumab and erlotinib) in patients with advanced pancreatic adenocarcinoma. The results of a phase I/II study. Eur J Cancer. 2014;50(8):1422–9.

    Article  CAS  PubMed  Google Scholar 

  125. Dean E, Middleton MR, Pwint T, Swaisland H, Carmichael J, Goodege-Kunwar P, et al. Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Br J Cancer. 2012;106(3):468–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12(3):256–62.

    Article  CAS  PubMed  Google Scholar 

  127. Kindler HL, Wroblewski K, Wallace JA, Hall MJ, Locker G, Nattam S, et al. Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Investig New Drugs. 2012;30(1):382–6.

    Article  CAS  Google Scholar 

  128. Fukasawa M, Korc M. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin Cancer Res. 2004;10(10):3327–32.

    Article  CAS  PubMed  Google Scholar 

  129. Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013;49(12):2633–42.

    Article  CAS  PubMed  Google Scholar 

  130. Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, et al. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol. 2014;74(2):379–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dragovich T, Burris H 3rd, Loehrer P, Von Hoff DD, Chow S, Stratton S, et al. Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am J Clin Oncol. 2008;31(2):157–62.

    Article  CAS  PubMed  Google Scholar 

  132. Tiltan Pharma Ltd. A clinical trial of anti-angiogenic drug combination Tl-118 for pancreatic cancer patients who are starting Gemcitabine treatment. In: Clinicaltrialsgov. Available in: https://clinicaltrials.gov/ct2/show/NCT01509911.

  133. Luo G, Long J, Zhang B, Liu C, Xu J, Ni Q, et al. Stroma and pancreatic ductal adenocarcinoma: an interaction loop. Biochim Biophys Acta. 2012;1826(1):170–8.

    CAS  PubMed  Google Scholar 

  134. Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6(4):1186–97.

    Article  CAS  PubMed  Google Scholar 

  135. Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S, et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun. 2010;403(3-4):380–4.

    Article  CAS  PubMed  Google Scholar 

  136. Sarker D, Molife R, Evans TR, Hardie M, Marriott C, Butzberger-Zimmerli P, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res. 2008;14(7):2075–81.

    Article  CAS  PubMed  Google Scholar 

  137. Galsky MD, Posner M, Holcombe RF, Lee KM, Misiukiewicz K, Tsao CK, et al. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;74(3):465–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Roswell Park Cancer Institute. Dovitinib Lactate, Gemcitabine hydrochloride, and Capecitabine in treating patients with advanced or metastatic solid tumors, pancreatic cancer and biliary cancers. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01497392.

  139. AB Science. A phase 3 study to compare efficacy and safety of Masitinib in combination with Gemcitabine, to Placebo in combination with Gemcitabine, in treatment of patients with advanced/metastatic pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/show/NCT00789633.

  140. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001;19(15):3447–55.

    Article  CAS  PubMed  Google Scholar 

  141. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer. 2002;87(2):161–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, et al. Phase Ib Study of PEGylated recombinant human Hyaluronidase and Gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22:2848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Halozyme Inc. A Study of PEGylated recombinant human Hyaluronidase in combination with Nab-Paclitaxel Plus Gemcitabine compared with Placebo Plus Nab-Paclitaxel and Gemcitabine in participants with Hyaluronan-High Stage IV previously untreated Pancreatic Ductal Adenocarcinoma. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT02715804.

  144. Therapeutics H. Study of Gemcitabine + PEGPH20 vs Gemcitabine alone in stage IV previously untreated pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01453153.

  145. Group SO. S1313, Combination chemotherapy with or without PEGPH20 in treating patients with newly diagnosed metastatic pancreatic cancer. In: Clinicaltrialsgov. Available through: https://clinicaltrials.gov/ct2/show/NCT01959139.

  146. Lu J, Yoshimura K, Goto K, Lee C, Hamura K, Kwon O, et al. Nanoformulation of Geranylgeranyltransferase-I inhibitors for cancer therapy: liposomal encapsulation and pH-dependent delivery to cancer cells. PLoS One. 2015;10(9):e0137595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Meng H, Zhao Y, Dong J, Xue M, Lin YS, Ji Z, et al. Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. ACS Nano. 2013;7(11):10048–65.

    Article  CAS  PubMed  Google Scholar 

  148. Kumar V, Mondal G, Slavik P, Rachagani S, Batra SK, Mahato RI. Codelivery of small molecule hedgehog inhibitor and miRNA for treating pancreatic cancer. Mol Pharm. 2015;12(4):1289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lucero-Acuna A, Jeffery JJ, Abril ER, Nagle RB, Guzman R, Pagel MD, et al. Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer. Int J Nanomedicine. 2014;9:5653–65.

    PubMed  PubMed Central  Google Scholar 

  150. Jiang G, Qiu W, DeLuca PP. Preparation and in vitro/in vivo evaluation of insulin-loaded poly(acryloyl-hydroxyethyl starch)-PLGA composite microspheres. Pharm Res. 2003;20(3):452–9.

    Article  CAS  PubMed  Google Scholar 

  151. Kobes JE, Daryaei I, Howison CM, Bontrager JG, Sirianni RW, Meuillet EJ, et al. Improved treatment of pancreatic cancer with drug delivery nanoparticles loaded with a novel AKT/PDK1 inhibitor. Pancreas. 2016;45:1158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Spring BQ, Bryan Sears R, Zheng LZ, Mai Z, Watanabe R, Sherwood ME, et al. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nat Nanotechnol. 2016;11(4):378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Galasso M, Sandhu SK, Volinia S. MicroRNA expression signatures in solid malignancies. Cancer J. 2012;18(3):238–43.

    Article  CAS  PubMed  Google Scholar 

  154. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  155. Iorio MV, Croce CM. MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol. 2009;27(34):5848–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 2005;37(7):766–70.

    Article  CAS  PubMed  Google Scholar 

  157. Carthew RW. Gene regulation by microRNAs. Curr Opin Genet Dev. 2006;16(2):203–8.

    Article  CAS  PubMed  Google Scholar 

  158. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65(16):7065–70.

    Article  CAS  PubMed  Google Scholar 

  159. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–47.

    Article  CAS  PubMed  Google Scholar 

  160. Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1(12):882–91.

    CAS  PubMed  Google Scholar 

  161. Jiao LR, Frampton AE, Jacob J, Pellegrino L, Krell J, Giamas G, et al. MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS One. 2012;7(2):e32068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yu S, Lu Z, Liu C, Meng Y, Ma Y, Zhao W, et al. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 2010;70(14):6015–25.

    Article  CAS  PubMed  Google Scholar 

  163. Zhao WG, Yu SN, Lu ZH, Ma YH, Gu YM, Chen J. The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis. 2010;31(10):1726–33.

    Article  CAS  PubMed  Google Scholar 

  164. Abue M, Yokoyama M, Shibuya R, Tamai K, Yamaguchi K, Sato I, et al. Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol. 2015;46(2):539–47.

    Article  CAS  PubMed  Google Scholar 

  165. Li A, Omura N, Hong SM, Vincent A, Walter K, Griffith M, et al. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 2010;70(13):5226–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ma C, Huang T, Ding YC, Yu W, Wang Q, Meng B, et al. MicroRNA-200c overexpression inhibits chemoresistance, invasion and colony formation of human pancreatic cancer stem cells. Int J Clin Exp Pathol. 2015;8(6):6533–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Lu Y, Lu J, Li X, Zhu H, Fan X, Zhu S, et al. MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell. BMC Cancer. 2014;14:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Singh S, Chitkara D, Kumar V, Behrman SW, Mahato RI. miRNA profiling in pancreatic cancer and restoration of chemosensitivity. Cancer Lett. 2013;334(2):211–20.

    Article  CAS  PubMed  Google Scholar 

  169. Ko AH, Tempero MA, Shan YS, Su WC, Lin YL, Dito E, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013;109(4):920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545–57.

    Article  CAS  PubMed  Google Scholar 

  171. Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, et al. Randomized phase II trial of Gemcitabine Plus TH-302 versus Gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2015;33(13):1475–81.

    Article  CAS  PubMed  Google Scholar 

  172. Tran EJ, King MC, Corbett AH. Macromolecular transport between the nucleus and the cytoplasm: Advances in mechanism and emerging links to disease. Biochim Biophys Acta. 2014;1843(11):2784–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90(6):1051–60.

    Article  CAS  PubMed  Google Scholar 

  174. Fung HY, Chook YM. Atomic basis of CRM1-cargo recognition, release and inhibition. Semin Cancer Biol. 2014;27:52–61.

    Article  CAS  PubMed  Google Scholar 

  175. Mirski SE, Sparks KE, Friedrich B, Kohler M, Mo YY, Beck WT, et al. Topoisomerase II binds importin alpha isoforms and exportin/CRM1 but does not shuttle between the nucleus and cytoplasm in proliferating cells. Exp Cell Res. 2007;313(3):627–37.

    Article  CAS  PubMed  Google Scholar 

  176. Abraham SA, Holyoake TL. Redirecting traffic using the XPO1 police. Blood. 2013;122(17):2926–8.

    Article  CAS  PubMed  Google Scholar 

  177. Alt JR, Gladden AB, Diehl JA. p21(Cip1) Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export. J Biol Chem. 2002;277(10):8517–23.

    Article  CAS  PubMed  Google Scholar 

  178. Henderson BR. Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol. 2000;2(9):653–60.

    Article  CAS  PubMed  Google Scholar 

  179. Ohtani N, Brennan P, Gaubatz S, Sanij E, Hertzog P, Wolvetang E, et al. Epstein-Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5. J Cell Biol. 2003;162(2):173–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Santiago A, Li D, Zhao LY, Godsey A, Liao D. p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1. Mol Biol Cell. 2013;24(17):2739–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wang Y, Wang Y, Xiang J, Ji F, Deng Y, Tang C, et al. Knockdown of CRM1 inhibits the nuclear export of p27(Kip1) phosphorylated at serine 10 and plays a role in the pathogenesis of epithelial ovarian cancer. Cancer Lett. 2014;343(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  182. Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013;122(17):3034–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Abdul Razak AR, Mau-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, et al. First-in-class, first-in-human phase I study of Selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. J Clin Oncol. 2016;34:4142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Barbara Ann Karmanos Cancer Institute. Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-stabilized nanoparticle formulation in treating patients with metastatic pancreatic cancer. In: Clinicaltrialsgov.Available through: https://clinicaltrials.gov/ct2/show/NCT02178436.

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA

    Maria Diab & Muhammad Saad Hamid

  2. Department of Oncology, Gastrointestinal Cancer Research, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA

    Ramzi M. Mohammad

  3. Department of Oncology, Department of Pharmacology, Wayne State University School of Medicine, Karmanos Cancer Institute, Hudson-Webber Cancer Research Center, Detroit, MI, USA

    Philip A. Philip

  4. Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA

    Asfar S. Azmi

Authors
  1. Maria Diab
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Saad Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ramzi M. Mohammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Philip A. Philip
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asfar S. Azmi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Asfar S. Azmi .

Editor information

Editors and Affiliations

  1. Department of Medical Oncology, Hacettepe University Institute of Cancer, Sihhiye, Ankara, Turkey

    Suayib Yalcin

  2. Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Philip A. Philip

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Diab, M., Hamid, M.S., Mohammad, R.M., Philip, P.A., Azmi, A.S. (2019). Novel Targeted Treatment Approaches in Pancreatic Cancer. In: Yalcin, S., Philip, P. (eds) Textbook of Gastrointestinal Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-18890-0_27

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-18890-0_27

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-18888-7

  • Online ISBN: 978-3-030-18890-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation